Epidemiology and Prevention
Trajectories of Entering the Metabolic Syndrome
The Framingham Heart Study
Oscar H. Franco, MD, DSc, PhD; Joseph M. Massaro, PhD; Jacky Civil, PhD; Mark R. Cobain, PhD;
Brendan O’Malley, PhD; Ralph B. D’Agostino, Sr, PhD
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Background—We evaluated the progression of the metabolic syndrome (MetS) and its components, the trajectories followed
by individuals entering MetS, and the manner in which different trajectories predict cardiovascular disease and mortality.
Methods and Results—Using data from 3078 participants from the Framingham Offspring Study (a cohort study) who attended
examinations 4 (1987), 5 (1991), and 6 (1995), we evaluated the progression of MetS and its components. MetS was defined
according to the Adult Treatment Panel III criteria. Using logistic regression, we evaluated the predictive ability of the
presence of each component of the MetS on the subsequent development of MetS. Additionally, we examined the probability
of developing cardiovascular disease or mortality (until 2007) by having specific combinations of 3 that diagnose MetS. The
prevalence of MetS almost doubled in 10 years of follow-up. Hyperglycemia and central obesity experienced the highest
increase. High blood pressure was most frequently present when a diagnosis of MetS occurred (77.3%), and the presence of
central obesity conferred the highest risk of developing MetS (odds ratio, 4.75; 95% confidence interval, 3.78 to 5.98).
Participants who entered the MetS having a combination of central obesity, high blood pressure, and hyperglycemia had a
2.36-fold (hazard ratio, 2.36; 95% confidence interval, 1.54 to 3.61) increase of incident cardiovascular events and a 3-fold
(hazard ratio, 3.09, 95% confidence interval, 1.93 to 4.94) increased risk of mortality.
Conclusions—Particular trajectories and combinations of factors on entering the MetS confer higher risks of incident
cardiovascular disease and mortality in the general population and among those with MetS. Intense efforts are required
to identify populations with these particular combinations and to provide them with adequate treatment at early stages
of disease. (Circulation. 2009;120:1943-1950.)
Key Words: cardiovascular diseases 䡲 Framingham study 䡲 metabolic syndrome 䡲 prevention 䡲 syndrome X
I
mprovements in healthcare and living conditions accompanied by the westernization of the global lifestyle have
given rise to pathological conditions such as the metabolic
syndrome (MetS).1
fundamental to accurately manage MetS to control current
global epidemics of CVD and diabetes mellitus,1,7 the
pathogenesis of the MetS and the manner in which its
components interact and evolve remain uncertain. Moreover, the trajectories followed by individuals entering the
MetS definition and the manner in which these trajectories
modify the lifetime experience of CVD and mortality are
poorly understood and have hardly been explored. These
factors may hamper the adequacy of management among
individuals with MetS. Further understanding of the development and progression of the MetS and its components
is required.
We sought to evaluate in adult populations from the
Framingham Offspring Study (FOS) the distribution and
progression of the MetS and its components, the trajectories
followed by those entering the MetS, and the potential effect
of individual trajectories on subsequent CVD and mortality.
Additionally, we evaluated whether these trajectories differ
by smoking status.
Clinical Perspective on p 1950
First labeled by Reaven in 1988 as “syndrome X,”2
different criteria exist to define the MetS.3– 6 In general, MetS
can be defined as the concomitant occurrence of multiple
metabolic irregularities that may include hypertension, dyslipidemia, abdominal obesity, insulin resistance, and microalbuminuria, depending on the selected definition.3– 6 Independently of the criteria chosen, the MetS has been widely
associated with an increased risk of diabetes mellitus,
cardiovascular disease (CVD), and cholesterol gallstones,
among other pathological conditions, in several studies.6 –9
For example, individuals with the MetS experience a
2-fold and 5-fold increase in the risk of developing CVD
and diabetes mellitus, respectively.6,7 Even though it is
Received February 2, 2009; accepted September 4, 2009.
From Unilever Corporate Research, Sharnbrook, UK (O.H.F., J.C., M.R.C., B.O.); University of Warwick, Warwick Medical School, Health Sciences
Research Institute, Coventry, UK (O.H.F.); Department of Mathematics/Statistics and Biostatistics, Boston University, Boston, Mass (J.M.M.); and the
National, Heart, Lung and Blood Institute’s Framingham Heart Study, Framingham, Mass (R.B.D.).
Guest Editor for this article was Robert H. Eckel, MD.
Reprint requests to Dr Oscar H. Franco, MD, DSc, PhD, Department of Public Health, B-160, Health Sciences Research Institute, University of
Warwick, Coventry, CV4 7AL, UK. E-mail [email protected]
© 2009 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.109.855817
1943
1944
Circulation
November 17, 2009
Methods
Data Sources
The original Framingham Heart Study cohort started between 1948
and 1951 with 5209 (45% men) residents of Framingham, Mass. The
FOS cohort is composed of the offspring and their spouses of the
original Framingham Heart Study and was examined beginning in
1971–1975 and approximately every 4 to 8 years since then. This
cohort consists of 5124 participants (48% men) aged 5 through 70
years at baseline. Further description of the Framingham Heart Study
and the FOS can be found elsewhere.10 –12
Study Sample
We selected data from participants attending each of examinations 4
(1987–1991), 5 (1991–1995), and 6 (1995–1998) and who were
evaluated for the presence/absence of the 5 components of the MetS
at each examination as defined below. Of 4019 participants who
attended examination 4, 730 people were excluded because they did
not attend all of examinations 4, 5, and 6; 211 were further excluded
because they had missing data on at least 1 of the components of the
MetS. In total, we analyzed data from 3078 participants of the FOS.
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Assessment of MetS
Presence of MetS was evaluated at examinations 4 though 6. To
define MetS, we used the Adult Treatment Panel III criteria, which
classifies individuals as having the MetS if they have at least 3 of the
following 5 components: (1) men with waist circumference (WC)
⬎40 inches (102 cm) or women with WC ⬎35 inches (88 cm); (2)
men with high-density lipoprotein (HDL) cholesterol ⬍40 mg/dL or
women with HDL cholesterol ⬍50 mg/dL; (3) triglycerides of ⱖ150
mg/dL; (4) high blood pressure (systolic blood pressure
ⱖ130 mm Hg or diastolic blood pressure ⱖ85 mm Hg or on
antihypertensive treatment); and (5) fasting glucose of ⱖ100 mg/
dL.6 This definition uses a cutoff level of fasting glucose of ⱖ100
mg/dL, as suggested recently by the American Diabetes Association
and the American Heart Association.
Assessment of CVD and Diabetes Mellitus
CVD was defined as the presence of 1 or more definite manifestations of coronary heart disease (angina pectoris, coronary insufficiency, myocardial infarction, and sudden or not sudden death as
consequence of coronary disease), congestive heart failure, stroke,
transient ischemic attack, and intermittent claudication. A panel of 3
physicians evaluated all events; the agreement of all 3 was required.
Diabetes mellitus was defined by having a random glycemia ⱖ200
mg/dL or being treated with insulin and/or oral antidiabetic agents.
More details on the evaluation of outcomes are available elsewhere.13
Progression of the MetS Components
To determine the progression of MetS and its components, we
measured the sex-pooled and sex-specific prevalence of MetS and of
each individual component at each of examinations 4 to 6. We then
grouped the individual components into pairs (there are 10 possible
pairs). For each pair, we identified the subgroup of participants who
at some point experienced both components of the pair for at least 1
of examinations 4 to 6. Then, of these participants, we determined
the frequency with which each component first presented itself at an
examination before the other component and the frequency at which
the 2 components first presented together (at the same examination).
Components and Triads: Frequency and
Prediction of MetS
In participants who did not have MetS at examination 4 but who
experienced MetS at examination 5 or 6 (n⫽776; 376 men and 400
women), we evaluated the sex-pooled and sex-specific incidence of
each component of the MetS and of each triad of factors that
permitted the diagnosis of MetS. “Triads” were defined as the
simultaneous combination of any 3 different components of the MetS
that would guarantee a diagnosis of MetS (a participant could have
experienced ⬎1 triad; eg, if a participant experienced a MetS
diagnosis because of high blood pressure, large WC, high triglycer-
ides, and low HDL, the participant would be considered as experiencing the following 3 triads: [1] high blood pressure, large WC, and
high triglycerides; [2] high blood pressure, large WC, and low HDL;
and [3] large WC, high triglycerides, and low HDL).
We assessed the age- and sex-adjusted relation between examination 4 prevalences of MetS components with the future (examination
5 or 6) occurrence (yes/no) of MetS. This assessment was performed
with the use of sex-pooled stepwise logistic regression, in which age
and sex were forced into the model as independent variables and with
the examination 4 presence (yes/no) of each of the 5 components as
candidates for entry into and remaining in the logistic model as
independent variables at a 0.05 level of significance. Incident MetS
developed by at least examination 5 and/or 6 was outcome. This was
performed twice: once for all participants in the study and once for
all participants without MetS at examination 4 (n⫽2356; 1058 men
and 1298 women). Assessments of the significance of the
component-by-sex (age and smoking) interaction were performed in
separate logistic models (1 model per component); factor-specific
age-adjusted logistic regression results (except for age) were inspected for components for which the factor-by-component interaction was significant at the 0.05 level.
Triads and Prediction of CVD and Mortality
We evaluated whether the incidence of the 5 most frequent triads has
an impact on each of incident CVD and mortality through 2007. This
assessment was performed with the use of stepwise sex-pooled Cox
proportional hazards regression (after assumption of proportionality
was tested and met), in which age and sex were forced into the model
as independent variables and with the incidence (yes/no) of each of
the 5 triads as candidates for entry into and remaining in the Cox
model as independent variables at a 0.05 level of significance. This
was performed twice: once for all participants in the study without
MetS at examination 4 regardless of subsequent incidence of MetS
and once for all participants without MetS at examination 4 who
experienced MetS by examination 6. Analysis on CVD incidence
further excluded participants with prevalent CVD at examination 4.
Participants not experiencing the outcome by 2007 are censored at
the end of 2007 or last known follow-up date, whichever is earlier.
Assessments of the significance of the triad-by-sex interaction were
performed in separate Cox regression analysis (1 model per triad);
sex-specific Cox regression results were inspected for triads for
which the sex-by-component interaction was significant at the 0.05
level.
Sensitivity Analysis
In addition to the different components of the MetS, smoking is
perhaps the most important factor that, if present, provides the
highest risk on incident CVD. Hence, we repeated the analyses of
frequency of components and triads and of prediction of MetS by
stratifying for smoking status (nonsmokers versus current and former
smokers).
All analyses were conducted with the use of SAS version 9.1 and
adjusted or stratified for age and/or sex. Potential factor-by-sex
interactions were evaluated. A 2-sided ␣ of 0.05 was used to claim
statistical significance.
All authors participated actively in all and each of the following
aspects for this article: conception and design or analysis and
interpretation of data; drafting of the article or revising it critically
for important intellectual content; and final approval of the version to
be published. Oscar H. Franco, as guarantor of this article, accepts
full responsibility for the work and/or the conduct of the study, had
access to the data, and controlled the decision to publish. The authors
had full access to and take full responsibility for the integrity of the
data. All authors have read and agree to the manuscript as written.
All authors declare having acted independently from the funders of
this project. Ethical approval was not required because this was a
secondary data analysis.
Results
Baseline Characteristics
The mean age of the population was 51.6 years at baseline
(examination 4). There were more women (51.6%); 6.4% and
Franco et al
Trajectories of Metabolic Syndrome
1945
Table 1. Characteristics of Study Sample at Examination 4, Sex Pooled (Participants Attending
Examinations 4 to 6 With Nonmissing MetS Data)
Characteristic
Age, y
Female sex
Body mass index, kg/m
Systolic blood pressure, mm Hg
Diastolic blood pressure, mm Hg
Overall (n⫽3078)*
No MetS (n⫽2356)*
MetS (n⫽722)*
51.6⫾9.9 (n⫽3078)
50.6⫾9.9 (n⫽2356)
54.9⫾9.1 (n⫽722)
1587 (51.6)
1298 (55.1)
289 (40.0)
26.7⫾4.7 (n⫽3070)
25.5⫾3.9 (n⫽2349)
30.6⫾4.8 (n⫽721)
126.2⫾18.3 (n⫽3078)
122.7⫾17.5 (n⫽2356)
137.7⫾16.1 (n⫽722)
79.1⫾9.9 (n⫽3077)
77.3⫾9.5 (n⫽2356)
84.9⫾8.8 (n⫽721)
Total cholesterol, mg/dL
205.5⫾38.5 (n⫽3078)
202.1⫾36.8 (n⫽2356)
216.9⫾41.7 (n⫽722)
HDL cholesterol, mg/dL
49.9⫾14.7 (n⫽3078)
53.4⫾14.1 (n⫽2356)
38.4⫾9.7 (n⫽722)
4.5⫾1.6 (n⫽3078)
4.0⫾1.3 (n⫽2356)
5.9⫾1.7 (n⫽722)
TC/HDL cholesterol, mg/dL
Triglycerides, mg/dL
120.4⫾90.7 (n⫽3078)
94.9⫾56.5 (n⫽2356)
Height, in
66.3⫾3.7 (n⫽3070)
66.1⫾3.7 (n⫽2349)
203.7⫾125 (n⫽722)
66.8⫾3.6 (n⫽721)
Weight, lb
167.8⫾35.7 (n⫽3078)
159.6⫾31.8 (n⫽2356)
194.7⫾34.4 (n⫽722)
WC, in
35.1⫾5.7 (n⫽3078)
33.6⫾5.1 (n⫽2356)
40.1⫾4.5 (n⫽722)
Hip, in
42.6⫾3.9 (n⫽721)
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39.9⫾3.7 (n⫽3073)
39.1⫾3.3 (n⫽2352)
Waist/hip ratio
0.9⫾0.1 (n⫽3073)
0.9⫾0.1 (n⫽2352)
0.9⫾0.1 (n⫽721)
Glucose, mg/dL
94.6⫾23.2 (n⫽3078)
89.9⫾12.8 (n⫽2356)
109.8⫾38.3 (n⫽722)
Ventricular rate
63.3⫾10.8 (n⫽3078)
62.5⫾10.3 (n⫽2356)
65.8⫾11.8 (n⫽722)
128 (4.2)
32/2356 (1.4)
96/721 (13.3)
17 (0.6)
12/2344 (0.5)
5/716 (0.7)
Hypertension treatment
507 (16.5)
246/2356 (10.4)
261/720 (36.3)
Lipid treatment
102 (3.3)
52/2355 (2.2)
50/718 (7.0)
Stage 1 hypertension
1056 (34.3)
582/2356 (24.7)
474/721 (65.7)
Stage 2 hypertension
620 (20.2)
313/2356 (13.3)
307/719 (42.7)
Smoking status
1313 (42.7)
999/2350 (42.5)
314/722 (43.5)
Prevalent CVD
199 (6.5)
113/2356 (4.8)
86/722 (11.9)
MetS
722 (23.5)
Diabetes mellitus
Definite LVH
Education
Some high school
High school
79/2087 (3.8)
51/1648 (3.1)
28/439 (6.4)
678/2087 (32.5)
505/1648 (30.6)
173/439 (39.4)
Some college/technical/business school
519/2087 (24.9)
419/1648 (25.4)
100/439 (22.8)
College graduate or higher
811/2087 (38.9)
673/1648 (40.8)
138/439 (31.4)
Values are mean⫾SD for continuous variables or percentages for categorical variables. Values in parentheses are percentages
unless indicated otherwise. TC indicates total cholesterol; LVH, left ventricular hypertrophy.
*n⫽number of participants who appeared for examinations 4 to 6.
4.2% had a previous diagnosis of CVD and diabetes mellitus,
respectively (Table 1). Mean levels of the components of the
MetS at baseline were as follows: WC 35.1 inches, systolic
blood pressure 126.2 mm Hg, diastolic blood pressure
79.1 mm Hg, HDL cholesterol 49.9 mg/dL, triglycerides
120.4 mg/dL, and fasting glucose 94.6 mg/dL.
Participants with MetS at examination 4 (722) were older
than those without it (54.9 versus 50.6 years; P⬍0.001) and
had a higher prevalence of diabetes mellitus (13.3% versus
1.4%; P⬍0.001) and CVD (11.9% versus 4.8%; P⬍0.001)
but were similar with respect to current/former smoking
status (43.5% versus 42.5%) (Table 1).
Prevalence and Progression of MetS
At examination 4, 722 (23.5%) of participants had a diagnosis
of MetS (Table 2). Prevalence of the 5 components of MetS
at examination 4 (for all participants) was as follows: 25.7%
had large WC, 38.7% had low HDL, 23.8% were hypertri-
glyceridemic, 48.4% were hypertensive, and 18.9% had
hyperglycemia (Table 2).
The prevalence of MetS increased from examination 4 to 5
by 10.6% and from examination 4 to 6 by 17.2% (Table 2).
Hyperglycemia experienced the highest increase from examination 4 to examination 6 (from 18.9% to 42.8%) followed
by central obesity (from 25.7% to 50.7%). High blood
pressure and hypertriglyceridemia each experienced an ⬇8%
increase in prevalence from examination 4 to 6, whereas low
levels of HDL decreased slightly from 38.7% at examination
4 to 36.4% at examination 6 (Table 2).
At examination 4, women and men had similar prevalences
of large WC and low HDL. Women had lower levels of
hypertriglyceridemia (16.8% versus 31.3%), high blood pressure (41.3% versus 56.0%), and hyperglycemia (13.8% versus 24.4%) than did men. Nevertheless, by examination 6,
women seemed to overtake men and even surpass them in the
case of prevalence of large WC. Although a 10% and 20%
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Circulation
November 17, 2009
Table 2. Prevalence and Progression of the MetS
(All Participants)
Progression
(Difference in Prevalence)
Prevalence, %
Sex and
Characteristic
Exam 4 Exam 5 Exam 6
4 to 5
5 to 6
4 to 6
17.2
Both
MetS
23.5
34.0
40.6
10.6
6.6
WC
25.7
35.0
50.7
9.3
15.7
25.0
HDL cholesterol
38.7
39.3
36.4
0.7
⫺3.0
⫺2.3
8.1
preceded the appearance of any other component (Table 3).
For example, of the 963 participants who ended up experiencing the HDL and hyperglycemia component simultaneously during at least 1 of examinations 4 to 6, 494 (51.3%)
of the participants had low levels of HDL before presenting
with hyperglycemia versus 108 (11.2%) who presented with
hyperglycemia first and 361 (37.5%) who presented with both
simultaneously at the examination. The next dominant component in terms of sequential appearance was high blood
pressure, and the least dominant was hyperglycemia (Table
3). Very similar findings were obtained when the population
was stratified by sex, except that high blood pressure became
the factor that preceded all the others among women (data not
presented).
Triglycerides
23.8
34.3
31.9
10.5
⫺2.3
Blood pressure
48.4
48.2
56.2
⫺0.2
8.1
7.8
Fasting glucose
18.9
33.2
42.8
14.3
9.6
23.9
MetS
18.2
29.4
37.4
11.2
7.9
19.2
Frequency of Factors and Triads on Entering the MetS
WC
22.9
36.6
57.5
13.6
20.9
34.5
HDL cholesterol
37.5
36.3
32.0
⫺1.2
⫺4.3
⫺5.5
Triglycerides
16.8
29.3
30.3
12.5
1.0
13.5
Blood pressure
41.3
43.0
51.4
1.7
8.4
10.1
Fasting glucose
13.8
25.6
32.9
11.8
7.3
19.1
MetS
29.0
39.0
44.1
9.9
5.1
15.0
WC
28.6
33.4
43.5
4.8
10.1
14.9
HDL cholesterol
39.9
42.6
41.0
2.7
⫺1.6
1.1
Triglycerides
31.3
39.6
33.7
8.2
⫺5.9
2.3
Blood pressure
56.0
53.7
61.4
⫺2.3
7.6
5.4
Fasting glucose
24.4
41.3
53.3
17.0
12.0
29.0
Of the participants without MetS at examination 4 but with
MetS at examination 5 or 6, high blood pressure was the
component that appeared most frequently with MetS, followed by WC, hypertriglyceridemia, hyperglycemia, and low
HDL (77.3%, 68.8%, 65.5%, 60.8%, 59.1%, respectively)
(Table 4). The order of levels of incident factors changed
when the population was stratified by sex. In women, central
obesity had the highest incidence level followed by high
blood pressure, hypertriglyceridemia, low HDL, and hyperglycemia. The sequential order in men was as follows: high
blood pressure, hyperglycemia, hypertriglyceridemia, low
HDL, and large WC (Table 4).
For participants without MetS at examination 4, the 5
triads (combination of any 3 components that guarantees
diagnosis with MetS by examination 5 or 6) with the
largest incidences were as follows, in order of descending
frequency: (1) WC⫹high blood pressure⫹hyperglycemia;
(2) HDL⫹high blood pressure⫹hypertriglyceridemia; (3)
WC⫹hypertension⫹hypertriglyceridemia; (4) high blood
pressure⫹hyperglycemia⫹hypertriglyceridemia; and (5)
HDL⫹WC⫹high blood pressure (Table 4). When stratified by sex, the triad of large WC⫹high blood
pressure⫹hyperglycemia still occurred most frequently
(Table 4), and 3 of the 5 most frequent triads for men and
women combined were also in the set of 5 most frequent
triads for each of men and women separately.
Women
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Men
difference in prevalence of high blood pressure and hyperglycemia remained between men and women at examination
6, women experienced a larger increase in prevalence of the
different components of the MetS from examination 4 to
examination 6 than did men. This was the case for all
components except for the prevalence of low HDL, which
decreased among women (37.5% to 32.0%) but remained
stable among men (Table 2).
Sequential Progression of Components of MetS
When low levels of HDL cholesterol were present at any
examination, having low levels of HDL cholesterol generally
Table 3. Sequential Progress of Pairs of MetS Components That Develop Subsequently
(Examinations 4, 5, and 6)
WC
Triglycerides
HDL Cholesterol
Blood Pressure
WC
Fasting Glucose
65 (362/191)
Triglycerides
53 (259/229)
HDL cholesterol
75 (378/125)
78 (346/99)
67 (377/188)
Blood pressure
72 (445/173)
73 (407/154)
52 (243/226)
82 (494/108)
82 (585/126)
Fasting glucose
Values not within parentheses are percentages. Row component first frequency/column component first frequency
is shown. Row component precedes column component percentage. Individual components are grouped into pairs
(there are 10 possible pairs). For each pair, we identified the subgroup of participants who at some point experienced
both components of the pair for at least 1 of examinations 4 to 6. Then, of these participants, we determined the
frequency with which each component first presented itself at an examination before the other component and the
frequency at which the 2 components first presented together.
Franco et al
Table 4. Frequency of MetS Triads/Factors on Entering MetS
(at 1 of Examination 5 to Examination 6) in People Without
MetS at Examination 4
Type and Combination/
Factor
All, n (%)*
Men, n (%)†
Women, n (%)†
BP
600 (77.3)
291 (77.4)1
309 (77.3)2
WC
534 (68.8)
216 (57.4)5
318 (79.5)1
508 (65.5)
3
260 (65.0)3
2
222 (55.5)5
459 (59.1)
4
228 (60.6)
231 (57.8)4
227 (29.3)
102 (27.1)1
125 (31.3)1
210 (27.1)
1
108 (27.0)3
5
Factor
TRIG
GLYC
HDL
472 (60.8)
248 (66.0)
250 (66.5)
Triad
WC, BP, GLYC
HDL, BP, TRIG
102 (27.1)
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WC, BP, TRIG
194 (25.0)
70 (18.6)
124 (31.0)2
BP, GLYC, TRIG
162 (20.9)
88 (23.4)3
74 (18.5)7
161 (20.7)
8
99 (24.8)4
7
97 (24.3)5
10
HDL, WC, BP
HDL, WC, TRIG
160 (20.6)
62 (16.5)
63 (16.8)
WC, GLYC, TRIG
129 (16.6)
47 (12.5)
82 (20.5)6
HDL, BP, GLYC
124 (16.0)
72 (19.1)4
52 (13.0)9
121 (15.6)
9
72 (18.0)8
6
50 (12.5)10
HDL, WC, GLYC
HDL, GLYC, TRIG
119 (15.3)
49 (13.0)
69 (18.4)
BP indicates blood pressure; GLYC, hyperglycemia; TRIG, hypertriglyceridemia; and WC, large waist circumference.
*Presented in sequential order from higher to lower.
†Superscript represents sequential order per sex from higher to lower.
Value of Examination 4 MetS Components
Prevalence in Predicting MetS
To evaluate the predictive ability of the presence of individual components at examination 4 on occurrence of MetS by
examinations 5 or 6, we conducted stepwise logistic regression analysis adjusting for age and sex, with the presence
(yes/no) of the 5 individual components at examination 4 as
candidates for entry into the model at the 0.05 significance
level (Table 5). All participants were included in this
analysis.
All MetS components significantly predicted MetS by
examination 5 or 6 in the presence of the other components,
with the presence of large WC conferring the highest effect
(odds ratio, 4.76; 95% confidence interval [CI], 3.79 to 5.98)
(Table 5). There was significant interaction with sex only for
high blood pressure (P⫽0.0465); the interaction is not due to
a difference in direction of blood pressure effect across sexes
but rather a difference in magnitude of effect.
Similar results were obtained for those free from MetS at
examination 4 (data not shown).
Predictive Value of Entering Combinations
(Triads) on Incident CVD and Mortality
The prevalence of the top 5 most frequent triads for entering
the MetS at examinations 5 or 6 (from Table 4) was assessed
for ability to predict the incidence of each of CVD and
all-cause mortality after baseline (defined as the examination
of incident MetS or examination 4 if no incident MetS) until
2007 (average follow-up period: 14 years). In total, there
were 244 CVD events for a rate of 11.0% (244/2217); this is
Trajectories of Metabolic Syndrome
1947
equivalent to 0.00769 CVD events per person-year of followup. Split by sex, we observed for men a 14.3% CVD rate
(139/974) and 0.01021 per person-year of follow-up, whereas
for women the rate was 8.4% (105/1243) and 0.00579 per
person-year of follow-up. The mortality rate for the overall
population was 8.3% (195/2356), with a rate of 0.00532
deaths per person-year of follow-up. This rate was higher for
men with 120/1058 (11.3%) and 0.00739 per person-year of
follow-up than for women with 75/1298 (5.8%) and 0.00368
per person-year of follow-up.
Age- and sex-adjusted stepwise Cox proportional hazards
regression, with the prevalence of each of the 5 triads as
candidates for entry at the 0.05 level of significance, was used
for this analysis. Participants with prevalent MetS were
excluded from these analyses; for the analysis on incident
CVD, participants with prevalent CVD at examination 4 were
also excluded.
Only 2 of the top 5 triads examined had a significant
impact on incident CVD (Table 6), with the triad of large
WC⫹high blood pressure⫹hyperglycemia conferring the
highest risk of developing CVD (hazard ratio, 2.36; 95% CI,
1.54 to 3.61). The other significant triad was that of
HDL⫹high blood pressure⫹hypertriglyceridemia. In addition, only these 2 triads had a significant effect on predicting
mortality. A combination of large WC⫹high blood
pressure⫹hyperglycemia bestowed a ⬎3-fold increased risk
of future mortality (hazard ratio, 3.09; 95% CI, 1.93 to 4.94),
whereas the combination of HDL⫹high blood pressure⫹hypertriglyceridemia represented an almost 3-fold increased
risk of mortality (hazard ratio, 2.73; 95% CI, 1.63 to 4.58).
None of the other top 5 triads (or any other below the top 5; data
not shown) had a significant effect on mortality (Table 6).
After the analyses were repeated for only individuals with
MetS by examination 5 or 6, only the large WC⫹high blood
pressure⫹hyperglycemia triad had a significant effect on
future CVD (hazard ratio, 1.64; 95% CI, 1.05 to 2.57), but no
triads had a significant effect on incident mortality.
Sensitivity Analyses
We repeated the analyses of the frequency of factors and
triads on entering the MetS by smoking status. Among
nonsmokers, high blood pressure remained the most present
factor when classified as having MetS, followed by large WC
(data not shown). In contrast, the most prevalent factor for
smokers was hypertriglyceridemia, followed by high blood
pressure. The order of the triads did not differ substantially by
smoking status, and the top 5 triads remained relatively the
same (data not shown).
Discussion
We identified different trajectories by which individuals enter
the MetS and determined that the specific trajectory followed
has a significant impact on subsequent risk of developing
CVD and on mortality. Participants who entered the MetS
having a combination of central obesity, high blood pressure,
and hyperglycemia had a 2.36-fold increase in incident CVD
events and a 3-fold increased risk of mortality in the general
population.
1948
Circulation
November 17, 2009
Table 5. Predictive Value of the Prevalence of Examination 4 Components of MetS on Incident MetS (Logistic Regression) (All
Participants at Examination 4 Followed Through Examination 6)*
Sex and Prevalence
Variable
Order Entered Into
Stepwise Model
Significance (Adjusting for
All Other Significant
Effects in Model)
Odds Ratio(Adjusting for
All Other Significant
Effects in Model)
Lower Limit
95% CI
Upper Limit
95% CI
Significance of
Interaction
With Sex
Both
Age
0
0.0012
1.02
1.01
1.03
Sex
0
0.1962
1.13
0.94
1.37
HDL
1
⬍0.0001
4.43
3.63
5.41
0.9380
WC
2
⬍0.0001
4.76
3.78
5.98
0.5193
BP
3
⬍0.0001
3.60
2.95
4.39
0.0465
TRIG
4
⬍0.0001
3.99
3.12
5.11
0.0890
GLYC
5
⬍0.0001
2.89
2.23
3.75
0.0572
Women
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Age
0
⬍0.0001
1.03
1.02
1.05
WC
1
⬍0.0001
5.12
3.61
7.28
HDL
0
⬍0.0001
4.87
3.65
6.51
BP
2
⬍0.0001
3.76
2.79
5.06
TRIG
3
⬍0.0001
5.10
3.29
7.90
GLYC
4
⬍0.0001
3.89
2.41
6.27
Men
Age
0
0.9937
1.00
0.98
1.01
HDL
1
⬍0.0001
4.21
3.19
5.56
WC
2
⬍0.0001
4.40
3.24
5.97
BP
3
⬍0.0001
3.25
2.48
4.27
TRIG
4
⬍0.0001
3.44
2.54
4.65
GLYC
5
⬍0.0001
2.56
1.87
3.51
BP indicates blood pressure; GLYC, hyperglycemia; TRIG, hypertriglyceridemia; and WC, large waist circumference.
*The c statistic for incident MetS is 0.86 for both men and women combined, 0.84 for men alone, and 0.88 for women alone.
Those with prevalent MetS having this combination of
factors represented a 1.64- and 1.58-fold higher risk of future
CVD events and mortality, respectively.
Among our participants, MetS was a highly prevalent
condition that increased dramatically in a relatively short
period of time. From 23.5% at baseline, the prevalence of
MetS almost doubled after 10 years of follow-up (40.6%).
Except for low levels of HDL, which remained stable over the
period examined, all other components experienced a substantial increase during the observation period. High levels of
fasting glucose more than doubled in prevalence as well as
large WC; the latter, in the case of women, almost tripled.
Although at baseline women had less prevalence of all
components of MetS than men, after 10 years of follow-up
they surpassed men on levels of central obesity and almost
caught up with all other factors. This could be due in part to
the age of our population and the effect that menopause may
have exerted among our participants during the observation.
A delayed increase in high blood pressure levels among
women also explains the higher increase in prevalence of
MetS compared with among men. High blood pressure
among women tended to lead all other factors, whereas for
men the factor that preceded all others was low levels of
HDL, reflecting perhaps different hepatic lipase activity and
lifestyles between sexes, an earlier decrease in physical
activity levels during middle age among men, or perhaps an
inherent effect of using different cutoff points for men and
women when defining low levels of HDL. Central obesity is
another factor that seemed to affect women more significantly than men. Levels of large WC in women not only
tripled during follow-up but were also the factor most often
present when MetS occurred, whereas for men large WC was
the factor that was least present, and high blood pressure had
the leading role. This may reflect a faster accumulation of
visceral fat among middle-aged women that seems to start at a
later age compared with men. When we compared the prevalence and presentation sequence of the MetS factors by smoking
status, high blood pressure remained as the most prevalent
factor, only surpassed among smokers by hypertriglyceridemia.
Irrespective of sex and smoking status, the combination of
large WC⫹high blood pressure⫹hyperglycemia was the
most prevalent triad, followed by the combination of low
HDL⫹high blood pressure⫹hypertriglyceridemia. High
blood pressure was not only the most frequent factor in the
analyses of frequencies irrespective of sex but played a
central role in the trajectories followed to enter the MetS.
Along with high blood pressure, 2 distinctive phenotypes
played a significant role: (1) a combination of central obesity
and dysregulation of glucose metabolism and (2) a phenotype
characterized by dyslipidemia. These 2 idiosyncratic phenotypes in combination with high blood pressure were also the
only ones to provide a significantly higher risk of future CVD
Franco et al
Trajectories of Metabolic Syndrome
1949
Table 6. Predictive Value of Entering Combinations (Triads) on Incident CVD and Mortality* (Cox Proportional Hazards Regression)
(All Analyses Include Participants Without CVD and MetS at Examination 4 Regardless of MetS Incidence by Examination 6)†
Order Entered Into
Stepwise Model
Significance (Adjusting for
All Other Significant
Effects in Model)
Hazard Ratio (Adjusting for
All Other Significant
Effects in Model)
Lower Limit
95% CI
Upper Limit
95% CI
Age
0
⬍0.0001
1.06
1.05
1.08
Sex
0
⬍0.0001
0.55
0.42
0.71
WC, BP, GLYC
1
⬍0.0001
2.36
1.54
3.61
0.2339
HDL, BP, TRIG
2
0.0079
1.94
1.19
3.16
0.0727
BP, GLYC, TRIG
3
0.4139
1.24
0.74
2.10
0.4546
WC, BP, TRIG
4
0.6433
0.86
0.46
1.61
0.2326
HDL, WC, BP
5
0.7962
0.92
0.49
1.74
0.3650
Age4
0
⬍0.0001
1.11
1.09
1.13
Sex
0
⬍0.0001
0.48
0.36
0.64
WC, BP, GLYC
1
⬍0.0001
3.09
1.93
4.94
0.6678
HDL, BP, TRIG
2
0.0001
2.73
1.63
4.58
0.2047
BP, GLYC, TRIG
3
0.3546
0.75
0.40
1.39
0.4646
HDL, WC, BP
4
0.5081
0.79
0.39
1.59
0.4377
WC, BP, TRIG
5
0.7729
1.11
0.55
2.21
0.0547
Outcome and Prevalence
Variable
Significance of
Interaction
With Sex
CVD
Mortality
Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017
BP indicates blood pressure; GLYC, hyperglycemia; TRIG, hypertriglyceridemia; and WC, large waist circumference.
*In total, there were 244 CVD events for a rate of 11.0% (244/2217); this is equivalent to 0.00769 CVD events per person-year of follow-up. Split by sex, we
observed for men a 14.3% CVD rate (139/974) and 0.01021 per person-year of follow-up, whereas for women the rate was 8.4% (105/1243) and 0.00579 per
person-year of follow-up. The mortality rate for the overall population was 8.3% (195/2356), with a rate of 0.00532 deaths per person-year of follow-up. This rate
was higher for men, with 120/1058 (11.3%) and 0.00739 per person-year of follow-up, than for women, with 75/1298 (5.8%) and 0.00368 per person-year of
follow-up.
†The c statistic for the mortality outcome was 0.78; for the CVD events, the c statistic was 0.68.
and mortality in any of the potential triads. No other combination of factors, other than these 2, had a significant effect
compared with the others. In the case of the combination of
high blood pressure⫹large WC⫹hyperglycemia, this effect
was also evident for populations with MetS, highlighting not
only its importance for the prevention of MetS, CVD, and
mortality but also the meaningful role that it might play in
adequate clinical management of those with established
MetS. These results also occurred irrespective of the presence
or absence of diabetes; when we repeated the analyses after
excluding those with diabetes, we found similar results (data
not presented).
The levels of prevalence of the MetS and its components
identified in our study fall well within the ranges of those
found and reported in previous publications.14 –20 Nevertheless, to our knowledge, our study is the first to not only
evaluate the levels of prevalence but also to elucidate the
progression of the syndrome and its factors, to identify and
characterize the different trajectories that populations follow
to enter the MetS, and to evaluate the effect that those
trajectories exert on future CVD events and mortality. Although 23% of our population were excluded because they
did not attend all examinations or had missing data on the
components of MetS, this study represents a wellcharacterized historic cohort with a long follow-up period
that allows us to not only elucidate the progression and
trajectories that populations follow while entering MetS but
also the effect that these trajectories have on future prognosis.
Participants included in the FOS were mainly white; therefore, our results may not apply to other ethnic groups, and any
generalization should be considered with care. A relevant
limitation of our study is that we could not evaluate the effect
of the different MetS components completely independent of
other risk factors of CVD and mortality, such as alcohol
consumption and socioeconomic status, because data for
these factors were incomplete, unreliable, or unavailable for a
large proportion of or for all of our population. It is possible
that part of the observed differences in future CVD and
mortality between the different triads could be explained by
the differences in alcohol intake and socioeconomic status.
However, the extent of the alcohol intake and socioeconomic
effect cannot be calculated with the available data.
Conclusions
MetS is a highly prevalent condition that is increasing dramatically and affects a large proportion of the middle-aged population. Not all individuals with MetS enter the syndrome with an
identical combination of factors. Certain trajectories and combinations of components confer higher risks of incident CVD and
mortality. Among these, 2 confer a significantly higher risk
compared with the others. Both have high blood pressure as a
central factor, 1 additionally has central obesity and hyperglycemia, and the other is characterized by dyslipidemia. Intense
efforts are required to identify populations with these particular
combinations and to provide them with adequate treatment at
early stages of disease.
1950
Circulation
November 17, 2009
Acknowledgments
We thank the participants of the Framingham Heart Study for their
continuous support.
9.
Sources of Funding
10.
This study was funded by Unilever plc. The funding organization did
not participate in the design and conduct of the study; collection,
management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript.
11.
Disclosures
12.
References
13.
None.
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CLINICAL PERSPECTIVE
Metabolic syndrome (MetS), the concomitant occurrence of multiple metabolic irregularities, has been associated with a
significant risk of future diabetes mellitus, cardiovascular disease, and mortality. Nevertheless, the manner in which the
syndrome evolves and the manner in which the future trajectories of disease develop remained uncertain. Using data from
3708 participants of the Framingham Offspring Study, we evaluated in adults the distribution and progression of the MetS
and its components, the trajectories followed by those entering the MetS, and the potential effect of individual trajectories
on the subsequent development of cardiovascular disease and mortality. MetS was defined according to the Adult
Treatment Panel III criteria. After 10 years of follow-up, the prevalence of MetS almost doubled. Hyperglycemia and
central obesity experienced the highest increase. High blood pressure was most frequently present when a diagnosis of
MetS occurred (77.3%), and presence of central obesity conferred the highest risk of developing MetS (odds ratio, 4.75;
95% confidence interval, 3.78 to 5.98). Participants who entered the MetS having a combination of central obesity, high
blood pressure, and hyperglycemia had a 236% increase in incident cardiovascular events and a 309% increased risk of
mortality. MetS is highly prevalent and is increasing dramatically; however, not all individuals who are diagnosed with
MetS enter the diagnosis with the identical combination of factors, and we identified 2 particular combinations of
components that confer higher risks of incident cardiovascular disease and mortality. Intense efforts are required to identify
populations with these particular combinations and to provide them with adequate treatment at early stages of disease.
Trajectories of Entering the Metabolic Syndrome: The Framingham Heart Study
Oscar H. Franco, Joseph M. Massaro, Jacky Civil, Mark R. Cobain, Brendan O'Malley and
Ralph B. D'Agostino, Sr
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Circulation. 2009;120:1943-1950; originally published online November 2, 2009;
doi: 10.1161/CIRCULATIONAHA.109.855817
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2009 American Heart Association, Inc. All rights reserved.
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